Epigenetics in Multiple Sclerosis-Related Cognition Impairment

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease that can result in various disabilities, including cognitive impairment. While the myelin sheath is traditionally considered the primary target, the gray matter of the cortex is also affected, contributing to cognitive dysfunction. This study explores the role of epigenetics in understanding the underlying pathological processes of MS and evaluates potential molecular patterns influencing cognition in MS patients. Epigenetics involves processes regulating gene expression in response to environmental stimuli, encompassing changes in DNA, histones, and microRNA without altering the nucleotide sequence. Understanding these epigenetic mechanisms may reveal new avenues for developing therapeutic interventions to manage cognitive dysfunctions in MS. Given the limited available data on the role of epigenetics in cognition in MS patients, this study aims to provide a comprehensive review of the existing literature on this subject.

1. Introduction

Epigenetics, a rapidly advancing scientific field, delves into the impact of environmental factors on genes and how organisms respond by orchestrating gene expression. These essential mechanisms not only play a pivotal role in developmental processes but also contribute to maintaining internal stability, commonly referred to as homeostasis. Organisms utilize these adaptive tools to effectively cope with and adjust to changes in their environment [1]. Epigenetic mechanisms encompass changes to the DNA structure or its associated proteins without modifying the underlying DNA nucleotide sequence. These modifications are often responsive to feedback and can subsequently play a role in either activating or repressing gene expression [2]. Gaining a thorough understanding of the principles of epigenetics and the complexities of its molecular mechanisms can enhance our comprehension of the development and progression of various diseases, including cancers, autoimmune conditions, neurodegenerative disorders, and psychiatric illnesses [3]. Studying epigenetics offers the potential for more effective treatments across diseases. This research focuses on multiple sclerosis (MS), a chronic autoimmune disease affecting young populations, characterized by inflammation and myelin degradation in the central nervous system [4]. Patients exhibit varied clinical presentations depending on the location of lesions in the CNS. Symptoms encompass double vision, blindness, muscle weakness, sensory loss, ataxia, nystagmus, bladder dysfunction, and psychiatric problems [5]. Recent research has brought to light the prominence of cognitive and memory impairment in individuals with MS [6].

While many studies have explored the role of epigenetics in cognition and cognitive issues in MS, evidence linking the two is limited. This study investigates how epigenetic modifications may influence gene expression related to neuroprotection, inflammation, and synaptic plasticity, potentially contributing to cognitive deficits in MS. The goal is to uncover the mechanisms of epigenetic regulation in MS, providing insights into the pathogenesis of cognitive impairments and suggesting avenues for novel therapeutic interventions.

2. Cognition impairment in MS

Cognition impairment is frequently observed in MS, with prevalence rates varying between 43% and 70% at different stages of the disease [7, 8, 9, 10].

Attention is a complex cognitive function that interconnects various processes, including alertness and vigilance. Impairments in attention are observed in an estimated 12–25% of patients with MS [11, 12]. It seems that in MS, the thalamus serves as the central gray matter area vital for attention-related tasks [13]. MS patients often experience challenges in both advanced and basic attention tasks [14]. Factors like the interconnectedness of attention with other cognitive areas, the influence of fatigue, and the variability in MS descriptions across studies can complicate accurate evaluations and conclusions regarding attention impairments [12, 15, 16].

Memory impairment stands out as a prevalent cognitive dysfunction observed in MS patients, with incidence rates ranging from 33% to 65% [11]. Predominantly, disruptions manifest in long-term memory, governing learning and recall functions, and working memory [16]. Despite prolonged discourse on the etiology of memory dysfunction in MS, definitive clarity remains elusive. Initial perspectives posited that deficits in retrieval from long-term storage were accountable for the observed long-term memory impairments, with encoding and storage capacities ostensibly unaffected [17, 18]. However, subsequent investigations advanced the notion that encoding and storage processes’ dysfunction precipitates memory deficits [19, 20]. It has also been revealed that among MS patients, significant impairments in maximum learning, and challenges in recovering from proactive and retroactive semantic interference effects, represent key deficiencies in episodic memory [21].

Visual perceptual functions involve recognizing and appropriately evaluating visual stimuli [16]. Limited research exists on this topic; however, a study by Lopes Costa et al. establishes a significant link between visual processing deficits in MS patients and reduced abilities in detecting visual stimuli, emphasizing a pronounced restriction in visual temporal processing capacity [22].

3. DNA methylation

DNA methylation, a well-studied epigenetic change in MS patients, regulates gene expression by methylating cytosine at the C5 position. DNA methyltransferase enzymes, including de novo types (Dnmt3a and Dnmt3b) and conventional types (Dnmt1), play distinct roles [23]. CpG islands, crucial in mammals, have higher CpG density and are present in about 70% of gene promoters. Methylation in these regions can suppress gene expression, vital for gene imprinting [24]. Studies on DNA methylation and cognition focus on synaptic plasticity, where neurons adapt based on stimuli. Feng and colleagues showed that the absence of Dnmt1 and Dnmt3a enzymes led to defects in hippocampal neuron plasticity, affecting learning and memory. This was achieved through genetic mutations in forebrain excitatory neurons [25].

3.1 DNA methylation in MS-related cognition impairment

Numerous studies have explored the impact of myelin sheath loss on synaptic plasticity and interneuron transmission in MS patients [26]. Pioneering this concept, Dutta and colleagues demonstrated that demyelination in the hippocampal neurons of MS patients suppresses the expression of genes associated with rapid inter-synaptic transmission. Additionally, they observed a reduction in the number of synapses in the demyelinated areas of the hippocampus in these patients [27].

Some studies have noted an increase in methylation and a decrease in demethylation enzymes mRNA during demyelination [28]. Siddiqa et al. focused on the upregulation of AKNA gene mRNA levels after demyelination, which regulates CD40 and CD40 ligands in microglia and macrophage cells. This increase leads to elevated TNF-α expression, contributing to neuronal death. Additionally, it was found that demyelination leads to increased TSS methylation in the WDR81 gene, crucial for neuronal survival, resulting in gene suppression [29, 30].

While there is limited data suggesting a direct link between DNA methylation and cognitive impairment in MS patients, we propose a hypothetical pathway based on our literature review that may be involved in this process.

Our initial hypothesis revolves around the aberrant expression of brain-derived neurotrophic factor (BDNF) in MS and its potential impact on cognition. BDNF, a vital member of the neurotrophins family, plays a pivotal role in synaptic plasticity, neuronal differentiation, and myelin sheath repair [31]. In MS patients with a more progressive disease course, there is observed hypomethylation and increased expression of BDNF, likely reflecting the neuronal response to tissue damage. Nociti have proposed that the expression level of this gene could serve as a prognostic indicator for disease progression in MS [32].

In a study comparing major depressive disorder patients and a healthy control group, higher BDNF methylation in most gene regions correlated with poorer cognitive performance. However, methylation of CpG site 10 in promoter I improved cognitive function, and CpG site 13 methylation in promoter IV was strongly linked to visual learning and memory [33]. Another study by Bakusic revealed that BDNF hypomethylation of promoter I is involved in anhedonia and impaired reward learning in depressed patients [34]. Shared biological pathways and therapeutic agents between MS and comorbidities suggest exploring common methylated genes like BDNF to uncover shared pathology.

Another hypothesis focuses on LGMN. Responsible for expressing the immune system regulator cysteine protease Legumain, LGMN’s hypomethylation and higher expression were observed in pathology-free areas of MS patients’ brains compared to the control group in the study by Huynh [35]. Additionally, Xia’s study highlights the link between LGMN suppression, increased longevity, and cognitive preservation. Overexpression of LGMN in nematodes led to early signs of cell aging and defects in learning and memory [36]. While the evidence supporting the relationship between LGMN methylation and cognition in MS is not as robust as previous hypotheses, the role of LGMN overexpression in both MS and cognitively impaired patients warrants further investigation.

4. Histone modifications in MS-related cognition impairment

In patients with multiple sclerosis (MS), elevated levels of histone acetylation, transcriptional inhibitors, and histone citrullination are observed. Aberrant citrullination in myelin proteins, particularly myelin basic protein (MBP), contributes to myelin instability and oligodendrocyte apoptosis. Citrullinated MBP is more prevalent in the normal-appearing white matter (NAWM) of MS patients. Increased PADI2 and PADI4 levels in the white matter suggest catalyzed citrullination by these enzymes. Abundant PADI, especially PADI4, in the nucleus of NAWM, justifies aberrant citrullination of H3, leading to the release of the proinflammatory cytokine TNF during demyelination. Histone methylation, occurring on lysine and arginine residues, has variable outcomes depending on the number and position of methyl groups. Some propose histone deacetylase inhibitors for MS treatment, but these may interfere with myelin development and repair. Thus, a more targeted treatment approach is recommended to balance potential benefits on neurons while protecting against detrimental effects on myelin production [37, 38].

Histone modification H3K4me3 plays a significant role in both memory formation and MS. Methylation at different histone sites can have varied effects on transcription, with H3K4me3 associated with increased transcription [2, 39]. Singhal’s study revealed reduced betaine concentration in the cortex of MS patients, correlating with decreased levels of H3K4me3 in neurons. This modification activates the transcription of genes related to the electron transport chain and cell respiration in neurons [40]. Additionally, studies suggest H3K4me3’s potential role in regulating BDNF expression, synaptic plasticity, and learning and memory formation [41]. Morse S.J.’s investigation linked learning with increased BDNF gene transcription and elevated H3K4me3 in the hippocampus, with the reversal of memory impairment in the aged hippocampus [42]. This suggests that dysregulation of baseline methylated histone levels, particularly H3K4me3, may contribute to memory dysfunction in MS patients [43].

A hypothesis can be on the role of H3K9me2, a transcriptional repressive marker, suggesting its involvement in memory impairment in MS patients [44]. H3K9me2 is linked to downregulating genes crucial for memory processes, potentially leading to deficits in memory [42]. SIRT1, involved in histone methylation and deacetylation, may play a role in this process [45]. Studies by Gupta-Agarwal show that increasing H3K9me2 levels in the lateral amygdala improves memory formation [46], while another study reveals elevated H3K9me2 levels in the hippocampus and entorhinal cortex during memory consolidation in rats [47]. These findings underscore the importance of investigating H3K9me2 in understanding memory impairment in MS patients.

Demyelination in MS involves antigen-presenting cells (APCs) presenting antigens to T cells, leading to T helper differentiation and subsequent activation by microglia in the CNS. Histone deacetylase inhibitors (HDACi) impact various cells in these pathways, promoting Treg cell function and inhibiting damaging Th1/17 cells [48]. Oligodendrocytes (OLGs) are influenced by HDACi, with more differentiated OLGs experiencing increased histone deacetylation, hindering differentiation, while undifferentiated oligodendrocyte precursor cells (OPCs) exhibit elevated histone acetylation. HDACi affects Tau in myelin, increasing histone acetylation, protecting microglia, and preventing myelin injury. HLA-DR expression, a genetic susceptibility factor in MS, is regulated by HDAC1. Studies in mice show that enhancing histone lysine acetylation through HDACi improves memory, synaptic plasticity, and fear extinction, offering potential therapies for anxiety disorders [49]. Acetylation of histones like H3K9 and H4K5 in young mice after contextual fear conditioning suggests a role in memory function [50]. HDAC2 reduction is implicated in memory and neuronal plasticity contrary to HDAC1, with Sirtuin 1 (SIRT1) [51], a deacetylase, playing a role in gene silencing [52]. Histone acetylation reduction in normal memory decline in the elderly involves transcription factors NF-κB and CREB, regulated by acetylation, with CREB binding protein (CBP) deletion impairing acetylation [50]. Inhibiting histone deacetylation activates BDNF promoter transcription. Jie’s study on rat hippocampal neurons reveals that aberrant H3K9 acetylation impairs synaptic plasticity and spatial memory, while HDAC inhibitors may offer protection against this memory impairment [53].

5. Micro RNAs in MS-related cognitive impairment

MiRNAs, recognized for their endogenous non-coding RNA structure, play a crucial role in posttranscriptional modulation of mRNA expression, influencing various biological processes [54]. These molecules are particularly important in maturation, impacting complex phenomena such as neuronal differentiation, synaptic plasticity, and memory formation [55, 56, 57]. Notably, dysregulation of miRNAs has been observed in neurodegenerative diseases and MS, prompting interest in their potential contribution to cognitive impairment in MS [58, 59]. While specific experimental studies on the impact of microRNAs on cognitive deficits in MS are currently lacking, existing knowledge on the role of epigenetics in MS and memory formation offers valuable insights.

MiR-233, located on the X chromosome, is implicated in contextual memory deficit and MS disease, directing attention to the transcription factor STAT5 and other regulators associated with MS-related inflammatory processes [60, 61, 62]. Fenoglio et al. observed a decrease in miR-223 expression in individuals with MS, correlating with disability and suggesting a potential link to neurodegeneration [63]. Ridolfi et al. documented elevated miR-223 expression in PBMCs, T regulatory cells, blood samples, and active MS lesions compared to controls [64]. Dysregulation of miR-223 is associated with key mechanisms in MS, including focal adhesion, T cell receptor signaling, and neurotrophin signaling [60]. Functioning as a neuroprotective microRNA, miR-223 is involved in contextual memory deficits and regulates neuronal cell death in the CA1 region of the hippocampus following transient global ischemia [65]. Overexpressing miR-223, but not NT-miRNA, reduces neuronal loss after a lethal NMDA insult in hippocampal neurons. Based on these findings, our hypothesis suggests that Mir-223 dysregulation contributes to memory impairment in MS patients.

MiR-9 plays a crucial role in cellular differentiation, exhibiting increased expression during the specialization of embryonic cells [66, 67]. In the context of MS, miR-9 shows upregulation in inactive lesions [68]. Its involvement extends to Parkinson’s disease (PD) and Alzheimer’s disease (AD), where altered expression is observed in patients’ blood serum and cerebrospinal fluid, serving as a reflection of the neurodegenerative disease status [69]. In AD, miR-9 is downregulated in cerebrospinal fluid, exhibiting a correlation with disease progression and neurofibrillary tangle severity (Braak stages) [70]. The dysregulation of miR-9 potentially contributes to the upregulation of neurofilament H and the downregulation of SIRT1, influencing AD pathogenesis [70]. These studies underscore the importance of exploring the role of miR-9 in AD, PD, and MS.

MiR-137, a crucial regulator in brain function, is implicated in MS, AD, and learning memory enhancement [71]. Its dysregulation in MS suggests potential diagnostic and prognostic biomarker utility, targeting HDAC9 and CACNA1C in neurodegenerative disorders [72]. In AD, miR-137 negatively regulates SPTLC1, impacting Aβ generation. Epigenetic factors like gender and diet influence miR-137 regulation in sporadic AD development [72]. Reduced miR-137 expression correlates with increased proBDNF translation, affecting synaptic remodeling and memory improvement [73]. Additionally, miR-137 modulates synaptic function at the hippocampal CA3-CA1 synapse by targeting GluA1 [74]. Overall, miR-137 expression changes may contribute to cognitive impairments in AD and MS patients.

MiR-22 displays differential expression in regulatory T cells of individuals with MS compared to healthy controls (HCs) [75], with heightened expression documented within active lesions [68]. It is upregulated in relapsing-remitting MS (RRMS) and elevated in mice’s spinal cords and peripheral lymphoid organs [76], impacting genes associated with PTEN-mediated signaling pathways [77]. Li et al.’s research highlights miR-22’s specific enrichment in aging brains, where it regulates mitochondrial complex subunits [78]. Additionally, miR-22 exhibits upregulation in active MS lesions, and while CD47-targeting miRNAs may decrease CD47 expression, further investigation is needed to understand their expression in other brain cell types [68].

6. Conclusion

Treating cognitive issues in individuals with MS is an urgent clinical necessity, as the disease’s progression poses significant challenges for patients, and effective treatment methods are currently lacking. The impairment of myelination is a key aspect of MS pathogenesis, and emerging evidence suggests a pivotal role for epigenetic processes in this context. Our comprehensive literature review explores the intricate interplay between epigenetics, cognition, and MS. Despite numerous studies on cognitive dysfunction in MS, a scarcity of data on the specific role of epigenetics and conflicting results characterize the existing literature. In this review, we propose hypotheses regarding potential epigenetic mechanisms contributing to cognitive impairment in MS patients, recognizing the existing gaps in knowledge. To address these limitations, future research should prioritize comprehensive clinical and trial studies, utilizing precise case-control designs, fine sampling, and PCR techniques targeting specific genes within the pathway. A more nuanced understanding of epigenetics holds promise for unveiling novel therapeutic strategies, leveraging cellular and molecular patterns to effectively address cognitive impairments in MS patients.

Acknowledgments

The authors would like to express their gratitude to Professor Sandro Misciagna for their invaluable guidance and supervision throughout the process of writing this chapter. This chapter was not supported by any grant.

Conflict of interest

The authors declare no conflict of interest.